21744-83-2Relevant articles and documents
Efficient synthesis of benzene-fused 6/7-membered amides: Via Xphos Pd G2 catalyzed intramolecular C-N bond formation
Xu, Zhou,Li, Ke,Zhai, Rongliang,Liang, Ting,Gui, Xiaodie,Zhang, Rongli
, p. 51972 - 51977 (2017/11/22)
An efficient approach for benzene-fused 6/7-membered amides via intramolecular amidation of aryl chlorides catalyzed by a Buchwald-Hartwig second generation Pd catalyst (Xphos Pd G2) has been successfully developed. This catalyst system allows the primary amides which have only modest nucleophilicity to be coupled successfully even with electron rich aryl chlorides in short reaction time. The intramolecular amidation reaction also has good chemoselectivity and excellent functional group compatibility.
Development of small-molecule Trypanosoma brucei N-myristoyltransferase inhibitors: Discovery and optimisation of a novel binding mode
Spinks, Daniel,Smith, Victoria,Thompson, Stephen,Robinson, David A.,Luksch, Torsten,Smith, Alasdair,Torrie, Leah S.,McElroy, Stuart,Stojanovski, Laste,Norval, Suzanne,Collie, Iain T.,Hallyburton, Irene,Rao, Bhavya,Brand, Stephen,Brenk, Ruth,Frearson, Julie A.,Read, Kevin D.,Wyatt, Paul G.,Gilbert, Ian H.
, p. 1821 - 1836 (2015/11/10)
The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei. HATs off to diversity! Screening a diverse library against Trypanosoma brucei N-myristoyltransferase (NMT) identified hits based on thiazolidinone and benzomorpholine scaffolds. X-ray crystallography of these compounds bound to Leishmania major NMT revealed novel active site binding conformations. Using the structural information, the benzomorpholine scaffold was optimised to a blood-brain barrier penetrant compound with activity against TbNMT of 0.002 μm.
Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose) polymerase inhibitors
Gangloff, Anthony R.,Brown, Jason,De Jong, Ron,Dougan, Douglas R.,Grimshaw, Charles E.,Hixon, Mark,Jennings, Andy,Kamran, Ruhi,Kiryanov, Andre,O'Connell, Shawn,Taylor, Ewan,Vu, Phong
supporting information, p. 4501 - 4505 (2013/08/15)
Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24 h following a single dose.
